A modular approach to a new class of monodentate chiral phosphorus ligands and their application in enantioselective copper-catalysed conjugate additions of diethylzinc to cyclohexenone

Article abstract of DOI:10.1002/ejoc.200400227

A new family of chiral phosphorus ligands (5) for use in enantioselective catalysis have been synthesised. The ligands contain the electron-poor bis(sulfonyl)diazaphospholidine moiety and possess a highly modular structure which is well suited to the synthesis of a library. A small library (23 members) of ligands 5 was prepared and tested in the enantioselective copper-catalysed conjugate addition of diethylzinc to cyclohexenone. Complete conversions were obtained with enantiomeric excesses (ee) of up to 75%. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400227

FULL PAPER
A Modular Approach to a New Class of Monodentate Chiral Phosphorus
Ligands and Their Application in Enantioselective Copper-Catalysed Conjugate
Additions of Diethylzinc to Cyclohexenone
[a]
[a]
[a]
[a,b]
Chiara Monti, Cesare Gennari,* Rebecca M. Steele, and Umberto Piarulli*
Keywords: Asymmetric catalysis / P ligands / Copper / Michael addition / Enones
A new family of chiral phosphorus ligands (5) for use
in enantioselective catalysis have been synthesised. The li-
gands contain the electron-poor bis(sulfonyl)diazaphos-
pholidine moiety and possess a highly modular structure
which is well suited to the synthesis of a library. A small
library (23 members) of ligands 5 was prepared and tested in
the enantioselective copper-catalysed conjugate addition of
diethylzinc to cyclohexenone. Complete conversions were
obtained with enantiomeric excesses (ee) of up to 75%.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
and effective ligands that contain O and N substituents on
[
3]
[5]
P (e.g. phosphoramidites 1, phosphonites 2, phosphites
[
6]
[7]
Transition-metal-catalysed asymmetric transformations 3, and 4, Figure 1) have been reported; these ligands
play an important role in the synthesis of complex organic have been successfully applied in a number of metal-cata-
molecules as well as in the industrial production of fine lysed asymmetric transformations.
[
1]
chemicals. In general, a chiral ligand is used to influence
both the reactivity of the metal ion (which can be enhanced
or reduced by formation of the metal complex) and direct
the stereochemical course of the catalysed reaction. Chiral
phosphorus ligands are among the most widely used chiral
ligands and have played a major role since the pioneering
work of Knowles, Kagan, and Noyori.[2] In particular, both
monophosphane and diphosphane ligands have been syn-
thesised, with the latter being the most widely represented
and successful of the ligands used in asymmetric catalysis
[
e.g. 1,4-bis(diphenylphosphanyl)-1,4-dideoxy-2,3-O-isopro-
pylidene--threitol (DIOP), bis[2-methoxyphenyl)phenyl-
phosphanyl]ethane (DIPAMP), and 2,2Ј-bis(diphenylphos-
phanyl)-1,1Ј-binaphthalene (BINAP), etc.][ In recent years,
2]
however, monophosphorus ligands have received renewed
interest, particularly those structures that possess one or
more PϪheteroatom bonds, such as chiral phosphoramid- Figure 1. General structures of phosphoramidite 1, phosphonite 2
ites,[
3,4]
[5]
[6Ϫ9]
and phosphite 3 and 4 ligands
phosphonites, phosphites,
and aminophos-
[
10]
phanes. Moreover, the creation of a PϪX bond is easier
synthetically than that of a PϪC bond. Hence, several new
In the search for new ligand structures that can be syn-
thesised through a modular scheme, and that are amenable
[
[
a]
b]
Dipartimento di Chimica Organica e Industriale, Centro di
Eccellenza C.I.S.I., Universit a` di Milano, Istituto di Scienze e
Tecnologie Molecolari (ISTM) del CNR,
[11]
to combinatorial exploitation,
we became interested in
bis(sulfonamido)-substituted phosphorus ligands of general
structure 5 (Figure 2), where R3 can be an alcohol, an
amine or an aryl substituent. A few ligands structurally
Via G. Venezian, 21, 20133 Milano, Italy
Fax: (internat.) ϩ 39-02-5031-4072
E-mail: cesare.gennari@unimi.it
[12]
[13]
Dipartimento di Scienze Chimiche e Ambientali, Universit a` related to 5 were recently reported by Hersh, Gimbert,
dell’Insubria,
[14]
and Pfaltz
and their co-workers. In particular, Hilgraf
Via Valleggio, 11, 22100 Como, Italy
Fax: (internat.) ϩ 39-031-238-6449
E-mail: umberto.piarulli@uninsubria.it
and Pfaltz’s chiral bis(sulfonyl)diazaphospholidineϪ
oxazoline ligands proved effective in promoting the pal-
Eur. J. Org. Chem. 2004, 3557Ϫ3565
DOI: 10.1002/ejoc.200400227
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3557

C. Monti, C. Gennari, R. M. Steele, U. Piarulli
FULL PAPER
ladium-catalysed asymmetric substitution of allylic acetates chiral; in the latter case, the C symmetry of the ligand is
2
3
with malonate anions with up to 99% enantiomeric excess retained only with a C -symmetric R group.
2
[
14]
(ee).
Figure 2. General structure of ligands 5
Here we report the synthesis of a small library of ligands
5
(23 members) and their application in the copper-cata-
lysed asymmetric conjugate addition of Et Zn to cyclohex-
enone.
2
Scheme 1. Synthetic approaches to ligands 5
Synthesis of Ligands 5
Results and Discussion
For the synthesis of ligands 5, three different diamine
Ligands 5 were chosen since they display several potential backbones were used (Scheme 2), namely (R,R)-1,2-di-
1
2
3
sites of diversity (R , R , R ) and their synthesis can be aminocyclohexane (6a), (R,R)-1,2-diphenylethylenediamine
readily accomplished through two highly modular synthetic (6b) and (S)-1,1Ј-binaphthyl-2,2Ј-diamine (6c). The sulfonyl
paths (Scheme 1). The structure allows for easy adjustment groups were thought to play a major role in determining the
of steric, electronic and conformational properties, by steric and electronic properties of ligands 5; for this reason,
2
3
modification of the sulfonamide (R ), the P (R ) and chiral diamines 6 were treated with a number of sulfonyl chlorides,
1
diamine (R ) substituents. In addition, sulfonamides are that is, methanesulfonyl chloride (7d), p-toluenesulfonyl
strongly electron-withdrawing and should, therefore, sub- chloride (7e), p-methoxybenzenesulfonyl chloride (7f), and
[
15]
For the R3
stantially affect the π-acceptor and σ-donor ability of the P 3,4-dimethoxybenzenesulfonyl chloride (7g).
atom, thereby affecting its ability to form metal complexes, moiety, a phenyl substituent and a variety of chiral and
and influencing the stability and catalytic activity of the achiral, primary and secondary amines 10hϪ10n were used.
complexes. As for the stereochemical properties, in the case
The synthesis of bis(sulfonamides) 8 was achieved by
of a C -symmetric diazaphospholidine ring, the P atom is treating diamines 6 with sulfonyl chlorides 7 under standard
2
3
not stereogenic. The P substituents (R ) can be achiral or conditions (Scheme 3) (see Exp. Sect.).
Scheme 2. Building blocks for the synthesis of the library of ligands 5
3558
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3557Ϫ3565

Chiral Phosphorus Ligands in Enantioselective Copper-Catalysed Conjugate Additions
FULL PAPER
An inverse approach (method C) was used in the case of
3
R ϭ phenyl, or with the bulky secondary amines 10h and
3
1
0n (Scheme 4). In this case, R PCl (11), either the com-
2
mercially available PhPCl (11o, Scheme 2) or the dichloro-
2
phosphinoamines 11h and 11n (obtained from the corre-
sponding amines 10h, 10n and PCl ), were treated with the
3
2
bis(sulfonamides) 8 (R ϭ pTol), derived from p-toluenesul-
fonyl chloride (7e). Bis(sulfonyl)diazaphospholidine forma-
Scheme 3. Synthetic scheme for the synthesis of ligands 5: method
3
3
A (R H) and method B (R Li)
tion was achieved either in the presence of a tertiary amine
3
(
R H ϭ 10h, 10n) or after deprotonation with 2 equiv. of
3
nBuLi (R ϭ Ph).
Bis(sulfonyl)diazaphospholidines 9 were prepared by the
reaction of bis(sulfonamides) 8 with PCl , either in the pres-
3
ence of a tertiary amine base (Et N) or after deprotonation
3
with 2 equiv. of nBuLi (Scheme 3). The deprotonation
method was always preferred since purer PϪCl derivatives
9
were obtained. Usually compounds 9 were not isolated
but were reacted in situ with excess primary or secondary
amines 10i, 10j, 10k, and 10l (method A); careful removal
of LiCl and amine hydrochlorides was performed by fil- Scheme 4. Synthesis of ligands 5 (method C)
tration through a PTFE membrane filter. After removal of
the volatiles under reduced pressure, ligands 5 were ob-
tained that were pure enough for subsequent use in cata-
lytic applications.
Contrary to our expectations, no reaction occurred when
we tried to introduce a PϪNMe moiety by the treatment of
2
An alternative synthetic pathway was chosen for the bis(sulfonamides) 8 with hexamethylphosphorous triamide
bulky secondary amines (10h, 10m, 10n, method B); in this [P(NMe ) ] at room temperature or at reflux in toluene.
2
3
case, the PϪCl derivatives 9 were reacted with the pre- This synthetic strategy had been applied with success to the
[
3a]
formed lithium salt of the amines. The corresponding li- synthesis of phosphoramidites 1 (R ϭ Me).
The desired
gands were then obtained after carrying out the work up dimethylamino derivatives (5adi, 5bdi, 5cdi, 5cfi and 5cgi)
procedure described above. Chromatographic purification were obtained in good yields by treating the PϪCl deriva-
could not be accomplished since ligands 5 are prone to hy- tives 9ad, 9bd, 9cd, 9cf and 9cg with a solution of dimethyl-
drolysis and need to be stored under nitrogen.
amine (3.3 equiv.) in THF.
Table 1. Synthetic methods, yields and 31P NMR chemical shifts of ligands 5
Entry
Ligand[a]
R1
R2
R3
Method
Yield [%]
P
δ [ppm]
1
2
3
4
5
6
7
8
9
5aeo
5aeh
5aen
5ado
5adi
5adh
5adj
5beo
5beh
5bdo
5bdi
5bdj
5ceo
5ceh
5cdo
5cdi
5cdj
5cdl
5cdk
5cdm
5cdn
5cfi
(CH
(CH
(CH
(CH
(CH
(CH
(CH
Ph
Ph
Ph
Ph
Ph
binaphth
binaphth
binaphth
binaphth
binaphth
binaphth
binaphth
binaphth
binaphth
binaphth
binaphth
2
2
2
2
2
2
2
)
)
)
)
)
)
)
4
4
4
4
4
4
4
pTol
pTol
pTol
Me
Me
Me
Ph
N(iPr)
N(MeCHPh)
Ph
NMe
N(iPr)
NHCH
Ph
N(iPr)
2
Ph
NMe
2
NHCH
Ph
N(iPr)
Ph
NMe
NHCH
NHCH(Me)Ph-(S)
NHCH(Me)Ph-(R)
N(MeCHPh)
N(MeCHPh)
NMe
NMe
C
C
C
C
A
B
A
C
C
C
A
A
C
C
C
A
A
A
A
B
82
96
95
84
75
42
90
74
80
89
94
89
98
98
99
98
85
98
75
94
98
84
88
95.6
99.3
100.4
95.8
102.7
99.8
2
2
-(R,R)
2
2
Me
2
2
2
Ph
Ph
Ph
134.9
107.6
110.1
108.2
112.5
101.4
131.7
129.4
129.8
125.5
166.6
107.9
113.5
146.3
146.4
127.1
127.2
pTol
pTol
Me
Me
Me
pTol
pTol
Me
Me
Me
Me
Me
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
2
2
2
-(S,S)
-(R,R)
2
B
A
A
4-MeO-C
3,4-(MeO) -C H
2 6 3
6
H
4
2
5cgi
2
Eur. J. Org. Chem. 2004, 3557Ϫ3565
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3559

C. Monti, C. Gennari, R. M. Steele, U. Piarulli
FULL PAPER
Based on these synthetic methodologies a small library
All the experiments were performed under identical con-
of 23 different ligands was prepared. Only some of all the ditions. Cu(OTf) (5 mol %) and the chiral ligand 5 (Cu/5
2
possible combinations (3 ϫ 4 ϫ 8 ϭ 96) were taken into ratio 1:2.2) were dissolved in toluene and stirred at room
consideration, and the choice was made following a sort of temperature for 1 h. The reaction mixture was then cooled
positional scanning approach[ (vide infra the enantio- to Ϫ20 °C and diethylzinc and cyclohexenone were added.
16]
selective copper-catalysed conjugate addition of diethylzinc The reactions were quenched with NH Cl after a standard
4
to cyclohexenone with ligands 5).
reaction time of 5 h, and the crude mixtures were analysed
Ligands 5 were characterized by H, 13C, and 31P NMR by chiral GC (see Exp. Sect.). Complete conversions
1
3
1
spectroscopy (Table 1). The P chemical shifts of ligands 5 (Ͼ 98%) were obtained for all the ligands studied.
are typical of phosphonite and phosphoramidite ligands, At the beginning of the screening, a small subset of li-
1
2
3
3
3
and depend on the different substituents (R , R , R ). In gands 5 was tested: we kept R constant (R ϭ Ph) and
3
1
particular, the P chemical shifts appear to be mostly influ- varied the scaffolds (6a, 6b and 6c) and the sulfonyl chlo-
enced by the nature of the diamine scaffold. In fact, the 31
rides (7d and 7e). The results are summarised in Table 2.
signals are shifted downfield in the order: 1,1Ј-binaphthyl- The enantioselectivities obtained were poor (max ee ϭ
,2Ј-diamine Ͼ 1,2-diphenylethylenediamine Ͼ 1,2-di- 35%), and indicated a slight preference in favour of ligands
P
2
2
aminocyclohexane.
with R ϭ MeSO (Entries 4Ϫ6).
2
Table 2. Screening of ligands 5[a]
Enantioselective Copper-Catalysed Conjugate Addition of
Diethylzinc to Cyclohexenone with Ligands 5
Ligand R1
R2
R3
ee [%][b] (abs. conf.)[c]
Entry
Trivalent phosphorus ligands that contain
PϪheteroatom bond have frequently been used in the en-
a
1
2
3
4
5
6
5ceo
5aeo
5beo
5cdo
5ado
5bdo
binaphth pTol Ph
0
(CH
Ph
binaphth Me
(CH
Ph
2
)
4
pTol Ph
5 (S)
antioselective copper-catalysed conjugate addition of di-
pTol Ph 25 (R)
Ph 17 (R)
Ph
Ph 35 (R)
alkylzinc reagents to enones.[
3,4,5c,7,10,17]
We chose the con-
jugate addition of diethylzinc to cyclohexenone (Scheme 5)
as a benchmark for our ligands, as this reaction is a useful
reference for evaluating the activity and enantioselectivity
of our catalytic system.
2
)
4
Me
Me
0
[a]
Cu(OTf)
2
(0.05 equiv.); ligand 5 (0.11 equiv.); Et
2
Zn (2.2 equiv.);
[b]
toluene; Ϫ20 °C; 5 h.
DACTBSβ, 25 m, film 0.25 µm, carrier H
Determined by GC: MEGADEX
(70 kPa). [ The absolute
c]
2
configuration was determined by chiral GC by comparison of the
retention times with those of an unbalanced mixture of known en-
antiomeric composition.
3
Given the poor results obtained with R ϭ Ph, we de-
cided to examine the results obtained with amine substitu-
ents. These results are summarised in Table 3.
2
Scheme 5. Conjugate addition of Et Zn to cyclohexenone, cata-
lysed by copper complexes of ligands 5
Table 3. Screening of ligands 5[a]
Entry
Ligand
R1
R2
R3
ee [%][b] (abs. conf.)[c]
1
2
3
4
5
6
7
8
9
5aeh
5adh
5beh
5ceh
5aen
5cdm
5cdn
5adj
5bdj
5cdj
5cdl
5cdk
5cdi
5adi
5bdi
5cfi
(CH
(CH
Ph
binaphth
(CH
binaphth
binaphth
(CH
Ph
binaphth
binaphth
binaphth
binaphth
(CH
Ph
2
2
)
)
4
p-Tol
Me
p-Tol
p-Tol
p-Tol
Me
Me
Me
Me
Me
Me
Me
Me
Me
N(iPr)
N(iPr)
N(iPr)
N(iPr)
N(MeCHPh)
N(MeCHPh)
N(MeCHPh)
NHCH
NHCH
NHCH
NHCH(Me)Ph (S)
NHCH(Me)Ph (R)
2
2
2
2
9 (R)
3 (R)
9 (R)
0
4
2
)
4
2
2
2
(S,S)
(S,S)
(R,R)
0
14 (S)
19 (R)
8 (S)
0
56 (R)
0
16 (R)
75 (R)
16 (R)
23 (R)
5 (R)
8 (R)
2
)
4
2
2
2
Ph
Ph
Ph
10
11
12
13
14
15
16
17
NMe
NMe
NMe
NMe
NMe
2
2
2
2
2
2
)
4
Me
4-MeO-C H
6 4
3,4-(MeO) -C H
2 6 3
binaphth
binaphth
5cgi
[
a]
[b]
Cu(OTf)
2
(0.05 equiv.); ligand 5 (0.11 equiv.); Et
2
Zn (2.2 equiv.); toluene; Ϫ20 °C; 5 h. Determined by GC: MEGADEX DACTBSβ,
2
5 m, film 0.25 µm, carrier H
2
(70 kPa). [c] The absolute configuration was determined by chiral GC by comparison of the retention
times with those of an unbalanced mixture of known enantiomeric composition.
3560  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 3557Ϫ3565

Chiral Phosphorus Ligands in Enantioselective Copper-Catalysed Conjugate Additions
FULL PAPER
It can be seen that both chiral and achiral bulky amines 50.28 MHz. Carbon chemical shifts are reported in ppm (δ) relative
to TMS with the respective solvent resonance as the internal stand-
ard (CDCl , δ ϭ 77.0). P NMR spectra were recorded with com-
3
plete proton decoupling with a Bruker Avance 400 spectrometer
operating at 162 MHz. Phosphorus NMR chemical shifts are re-
afford only low enantioselectivities (Entries 1Ϫ7). In ad-
3
1
dition, when chiral amines were used (Entries 6 and 7), the
sense of induction was found to depend on the absolute
configuration of the amine and a very minor contribution
from the binaphthyl moiety was observed (the ees with li-
gands 5cdm and 5cdn are very similar in magnitude). When
primary amines were used, a substantial improvement in
3 4
ported in ppm (δ) relative to external 85% H PO at 0 ppm (posi-
tive values downfield). Infrared spectra were recorded with a Jasco
Ϫ1
FT/IR-300E infrared spectrometer; peaks are reported in cm
.
Optical rotation values were measured with a PerkinϪElmer 241
the enantioselectivity was noticed in the case of benzyl- polarimeter with a 1-dm cell at the sodium D line; [α] values are
D
2
-1
amine (cf. Entry 10, ee ϭ 56%, with Entries 6, 7, 11, and given in units of 10deg·cm ·g . Gas chromatography was per-
1
2). By comparing Entries 8Ϫ10, the 1,1Ј-binaphthyl-2,2Ј- formed with a Dani GC-6500 instrument equipped with a flame
ionization detector. Enantiomeric excesses were determined by chi-
diamine was identified as the best scaffold. Dimethylamine
derived ligands gave optimal results (Entries 13Ϫ17) and
an enantiomeric excess as high as 75% was obtained with
ligand 5cdi.
ral GC using a MEGADEX DACTBSβ, OV 1701 capillary column
25 m, film 0.25 µm) in comparison with a racemic sample. Melting
point determination of ligands 5 (powders) could not be ac-
complished since they are unstable and tend to decompose (hy-
drolysis and oxidation) when exposed to air or heated. The follow-
(
ing compounds were synthesised as originally reported: (1R,2R)-
Conclusions
[18,19]
trans-1,2-bis(p-tolylsulfonylamino)cyclohexane (8ae),
trans-1,2-diphenyl-N,NЈ-bis(p-tolylsulfonyl)ethylenediamine (8be),
(1R,2R)-
[19]
In summary, we have developed a new family of chiral
[20]
(
S)-N,NЈ-bis(p-tolylsulfonyl)-1,1Ј-binaphthyl-2,2Ј-diamine (8ce),
[
21]
phosphorus ligands (5) for use in enantioselective catalysis. (1R,2R)-trans-1,2-bis(methylsulfonylamino)cyclohexane (8ad),
The ligands contain the electron-poor bis(sulfonyl)diaza- (1R,2R)-trans-1,2-diphenyl-N,NЈ-bis(methylsulfonyl)ethylene-
phospholidine moiety and possess a highly modular struc- diamine (8bd),[
21,22]
(S)-N,NЈ-bis(methylsulfonyl)-1,1Ј-binaphthyl-
(8cd),[23]
(1R,2R)-trans-1,2-bis(trifluoromethyl-
sulfonylamino)cyclohexane,
2,2Ј-diamine
ture which is well suited to the synthesis of a library. A
small library (23 members) of ligands 5 was prepared and
tested in the enantioselective copper-catalysed conjugate
addition of diethylzinc to cyclohexenone. Complete conver-
sions were obtained with enantiomeric excesses of up to
[21]
(1R,2R)-trans-1,2-diphenyl-N,NЈ-
[21]
bis(trifluoromethylsulfonyl)ethylenediamine,
(S)-N,NЈ-bis(tri-
fluoromethylsulfonyl)-1,1Ј-binaphthyl-2,2Ј-diamine,[
23]
(S)-N,NЈ-
[20]
bis(p-methoxyphenylsulfonyl)-1,1Ј-binaphthyl-2,2Ј-diamine (8cf),
and
(S)-N,NЈ-bis(3,4-dimethoxyphenylsulfonyl)-1,1Ј-binaphthyl-
7
1
5% (with ligand 5cdi). In particular, ligands containing the
,1Ј-binaphthyl-2,2Ј-diamine scaffold gave superior results,
[20]
2,2Ј-diamine (8cg).
[Bis(α-methylbenzyl)amino]phosphorous Dichloride (11m, 11n):
followed by 1,2-diphenylethylenediamine and 1,2-diamino-
cyclohexane. As for the sulfonyl chlorides, it appears that
methanesulfonyl chloride derivatives afford better results
than arylsulfonyl chloride derivatives. It is also evident that
small amine substituents at phosphorus are preferable.
Work is in progress in our laboratories to apply this class
of ligands to other enantioselective transformations.
Bis(α-methylbenzyl)amine (2 mmol, 458 µL) was dissolved in dry
THF (5 mL), under argon, and cooled to Ϫ78 °C. nBuLi (1.6 
in hexanes, 2.0 mmol, 1.25 mL) was slowly added. After 1 h, the
temperature was allowed to rise to room temperature. After 2 h,
3
the reaction mixture was cooled to Ϫ78 °C, and PCl (2 mmol, 175
µL) was added dropwise. The reaction was stirred, overnight, and
the temperature was allowed to rise to room temp. THF was re-
moved, dry toluene was added and the mixture was filtered through
a PTFE membrane filter to remove LiCl. The solvent was removed
3
1
Experimental Section
under reduced pressure, and the product was checked by P NMR
spectroscopy, and stored under an inert atmosphere at 0 °C.
General Remarks: All reactions were carried out in flame-dried
glassware with magnetic stirring under argon. All commercially
available reagents were used as received. The solvents were dried
by distillation over the following drying agents and were transferred
[
(S,S)-Bis(α-methylbenzyl)amino]phosphorous Dichloride (11m):
1
Yellow viscous oil (587 mg, 90% yield). H NMR (200 MHz,
): δ ϭ 7.65 (d, J ϭ 6.9 Hz, 2 H, ArH), 7.14 (m, 8 H, ArH),
.84 (m, 1 H, CH), 3.81 (m, 1 H, CH), 2.03 (d, J ϭ 6.8 Hz, 3 H,
6 6
C D
4
CH
under nitrogen: CH
2
Cl
2 2 2
(CaH ), THF (Na), Et O (Na), toluene
1
3
3
), 1.51 (d, J ϭ 7.2 Hz, 3 H, CH
): δ ϭ 138.4, 137.8, 129.3, 129.1, 127.5, 126.8, 44.5, 22.0 ppm.
P NMR (162 MHz, C ): δ ϭ 166.8 ppm.
3
) ppm. C NMR (100 MHz,
(
Na), pyridine (CaH
2
). Reactions were monitored by analytical
6 6
C D
thin-layer chromatography (TLC) using silica gel 60 F254 precoated
glass plates (0.25 mm thickness). Visualization was accomplished
by irradiation with a UV lamp and/or by staining with a ceric am-
monium molybdate (CAM) solution. Flash column chromatogra-
3
1
6
D
6
[(R,R)-Bis(α-methylbenzyl)amino]phosphorous Dichloride (11n):
1
Yellow viscous oil (587 mg, 90% yield). H NMR (200 MHz,
): δ ϭ 7.64 (d, J ϭ 7.1 Hz, 2 H, ArH), 7.14 (m, 8 H, ArH),
.86 (m, 1 H, CH), 3.82 (m, 1 H, CH), 2.03 (d, J ϭ 6.8 Hz, 3 H,
˚
phy was performed using silica gel 60A, particle size 40Ϫ64 µm.
6 6
C D
1
H NMR spectra were recorded with a Bruker Avance 400 spec-
4
CH
trometer operating at 400.13 MHz, and with a Bruker AC 200 spec-
trometer operating at 200 MHz. Proton chemical shifts are re-
ported in ppm (δ) with the solvent as reference relative to tetra-
13
3
), 1.51 (d, J ϭ 7.1 Hz, 3 H, CH
): δ ϭ 138.4, 137.8, 129.3, 129.1, 127.5, 126.8, 44.5, 22.0 ppm.
P NMR (162 MHz, C ): δ ϭ 166.8 ppm.
3
) ppm. C NMR (100 MHz,
6 6
C D
31
6
D
6
methylsilane (TMS) employed as the internal standard (CDCl
.26 ppm). 13C NMR spectra were recorded with complete proton
decoupling with a Bruker Avance 400 spectrometer operating at
3
δ ϭ
7
(Diisopropylamino)phosphorous Dichloride (11h): In a dry three-
necked flask, under argon, solution of diisopropylamine
00.56 MHz, and with a Bruker AC 200 spectrometer operating at (50 mmol, 7 mL) in dry diethyl ether (20 mL) was cooled to Ϫ10
a
1
Eur. J. Org. Chem. 2004, 3557Ϫ3565
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3561

C. Monti, C. Gennari, R. M. Steele, U. Piarulli
C. Phosphorus trichloride (29.4 mmol, 2.57 mL) was added drop- J ϭ 8.2 Hz, 2 H, ArH), 6.90 (d, J ϭ 8.1 Hz, 2 H, ArH), 6.68 (d,
FULL PAPER
°
wise over a period of 30 min. The reaction mixture warmed to
room temperature and stirred overnight. The precipitate was then
removed by vacuum filtration; the solution was collected, and the
solvent removed under reduced pressure. The crude product was
J ϭ 8.1 Hz, 2 H, ArH), 3.99Ϫ3.89 (m, 2 H, 2 ϫ CHN), 4.00Ϫ3.80
(m, 1 H, CyH), 2.78Ϫ2.65 (m, 2 H, CyH), 2.34Ϫ2.27 (m, 1 H,
CyH), 2.02 (s, 3 H, CH
12 H, 4 ϫ CH ), 1.50Ϫ0.40 (m, 6 H, CyH) ppm. C NMR
(100 MHz, C ): δ ϭ 143.0, 142.1, 129.4, 129.1, 128.1, 126.5, 66.1,
3 3
), 1.92 (s, 3 H, CH ), 1.65 (d, J ϭ 6.7 Hz,
1
3
3
purified by vacuum distillation (72 °C at 0.5 Torr). Colourless vis-
6 6
D
1
31
cous oil (2.50 g, 43% yield). H NMR (200 MHz, C
(
6
D
6
): δ ϭ 4.65 63.4, 48.4, 48.3, 31.4, 29.0, 24.2, 24.0, 23.6, 20.9, 20.8 ppm.
P
1
3
m, 2 H, 2 ϫ CH), 0.99 (d, J ϭ 6.8 Hz, 12 H, 4 ϫ CH
3
) ppm.
C
NMR (162 MHz, C
6
D
6
): δ ϭ 99.3 ppm. IR (film): ν˜ ϭ 1634, 1599,
3
1
Ϫ1
25
NMR (100 MHz, C
6
D
6
): δ ϭ 48.3, 48.0, 23.1, 23.0 ppm. P NMR 1347, 1323, 1202, 1156, 1114, 1090 cm . [α]
D
ϭ Ϫ56 (c ϭ 0.99,
(
162 MHz, C D ): δ ϭ 170.2 ppm. THF). MS (FAB, glycerol): m/z (%) ϭ 552 (65), 536 (25), 451 (100),
6 6
1
5
39 3 4 2
54 (35), 139 (25). HRMS (ESI): calcd. for C26H N O PS :
52.2120 [M ϩ H] ; found 552.2120.
General Procedure for the Synthesis of Ligands 5, Method A: In a
Schlenk tube under argon, the bis(sulfonamide) 8 (1 mmol) was
dissolved in dry THF (4 mL), and cooled to Ϫ78 °C. nBuLi (1.6
ϩ
1
Ligand 5aeo: Method C, white powder (217 mg, 82%). H NMR
): δ ϭ 8.40Ϫ8.36 (m, 2 H, PhH), 8.04 (d, J ϭ 8.2

6 6
in hexanes, 2.1 mmol, 1.30 mL) was slowly added, and after 30 (400 MHz, C D
min the temperature was allowed to rise to room temperature. After Hz, 2 H, ArH), 7.53 (d, J ϭ 8.2 Hz, 2 H, ArH), 7.29Ϫ7.15 (m, 3
2
h, the reaction mixture was cooled to Ϫ78 °C, and PCl
3
H, PhH), 6.88 (d, J ϭ 8.1 Hz, 2 H, ArH), 6.67 (d, J ϭ 8.1 Hz, 2
H, ArH), 3.33Ϫ3.27 (m, 1 H, CyH), 2.92Ϫ2.88 (m, 1 H, CyH),
2.68Ϫ2.62 (m, 1 H, CyH), 2.49Ϫ2.45 (m, 1 H, CyH), 2.05 (s, 3 H,
(1.05 mmol, 92 µL) was added dropwise. The temperature was then
allowed to slowly rise to room temp. After 2 h, the reaction mixture
containing the bis(sulfonamide)PCl intermediate was cooled to
3 3
CH ), 1.96 (s, 3 H, CH ), 1.40Ϫ1.30 (m, 1 H, CyH), 1.27Ϫ1.23 (m,
Ϫ78 °C, and the amine [dimethylamine (2  in THF, 3.3 mmol, 1 H, CyH), 1.14Ϫ1.09 (m, 1 H, CyH), 0.99Ϫ0.88 (m, 1 H, CyH),
1
3
1.65 mL), benzylamine (3.3 mmol, 360 µL), α-methylbenzylamine
0.66Ϫ0.55 (m, 1 H, CyH), 0.45Ϫ0.35 (m, 1 H, CyH) ppm.
): δ ϭ 143.9, 143.2, 140.9, 135.7, 130.6,
130.4, 130.1, 129.8, 129.2, 127.2, 68.0, 65.3, 32.4, 28.5, 23.9, 21.5,
C
(
3.3 mmol, 421 µL)] was added dropwise under argon. After 2 h, NMR (100 MHz, C D
6 6
the temperature was allowed to rise to room temperature, and the
mixture was stirred overnight. The solvent and excess amine were
removed under reduced pressure. Dry toluene was added, the reac-
tion mixture was filtered through a PTFE membrane filter under
argon to remove LiCl, and the solvent was removed.
3
1
21.4 ppm. P NMR (162 MHz, C
ν
˜
6 6
D ): δ ϭ 95.6 ppm. IR (film):
Ϫ1
25
ϭ 1645, 1597, 1343, 1323, 1161, 1112, 1088 cm . [α]D ϭ Ϫ35.35
(c ϭ 1.01, THF). HRMS (ESI): calcd. for C26
551.1204 [M ϩ Na] ; found 551.1185.
H
29
N
2
4 2
NaO PS :
ϩ
1
Ligand 5aen: Method C, yellow powder (321 mg, 95%). H NMR
(
2
Method B: In a Schlenk tube under argon, the bis(sulfonamide) 8
400 MHz, C
H, 2 ϫ CHN), 3.65Ϫ3.59 (m, 1 H, CyH), 2.95Ϫ2.45 (m, 2 H,
CyH), 2.34Ϫ2.30 (m, 1 H, CyH), 2.09 (s, 3 H, ArCH ), 2.06 (s, 3
H, ArCH ), 1.95 (s, 6 H, 2 ϫ CH ), 1.90Ϫ0.40 (m, 6 H, CyH) ppm.
C NMR (100 MHz, C ): δ ϭ 143.1, 142.6, 142.1, 142.0, 129.5,
29.1, 128.8, 128.0, 126.8, 126.7, 57.3, 55.2, 31.3, 28.5, 25.5, 25.0,
6 6
D ): δ ϭ 7.62Ϫ6.85 (m, 18 H, ArH), 3.79Ϫ3.77 (m,
(0.5 mmol) was dissolved in dry THF (2 mL), and cooled to Ϫ78
°C. nBuLi (1.6  solution in hexanes, 1.05 mmol, 656 µL) was
slowly added, and after 30 min the temperature was allowed to rise
to room temperature. After 2 h, the reaction mixture was cooled to
Ϫ78 °C, and PCl (0.52 mmol, 46 µL) was added dropwise. The
3
3
3
3
1
3
6
D
6
1
2
temperature was then allowed to slowly rise to room temp. After 2
h, the reaction mixture containing the bis(sulfonamide)ϪPCl inter-
mediate was cooled to Ϫ78 °C. Meanwhile the amine (0.55 mmol)
was dissolved in dry THF (0.5 mL), cooled to Ϫ78 °C, treated with
nBuLi (1.6  solution in hexanes, 0.575 mmol, 359 µL) and stirred
at room temp. for 1 h. The lithium salt of the amine was then added
dropwise to the reaction mixture, under argon, at Ϫ78 °C. After 2
h, the temperature was allowed to rise to room temperature, and
the reaction was stirred overnight. The solvent was removed under
reduced pressure. Dry toluene was added, the reaction mixture was
filtered through a PTFE membrane filter under argon to remove
LiCl, and the solvent was removed.
3
1
6 6
3.4, 20.9, 20.8 ppm. P NMR (162 MHz, C D ): δ ϭ 100.4 ppm.
Ϫ1
25
IR (film): ν˜ ϭ 1653, 1598, 1159, 1118, 1076 cm . [α]
1.00, THF). HRMS (ESI): calcd. for fragment
NaO : 445.1232; found 445.1247.
Ligand 5adh: Method B, white powder (84 mg, 42%). 1H NMR
400 MHz, C ): δ ϭ 3.68Ϫ3.64 (m, 2 H, CyH), 3.44Ϫ3.39 (m, 2
H, CHN), 3.24 (s, 3 H, SO CH ), 3.22 (s, 3 H, SO CH ), 2.61Ϫ2.48
m, 2 H, CyH), 1.98Ϫ1.92 (m, 2 H, CyH), 1.66Ϫ1.60 (m, 2 H,
CyH), 1.48 (d, J ϭ 6.5 Hz, 12 H, 4 ϫ CH ), 1.44Ϫ1.38 (m, 2 H,
): δ ϭ 57.3, 47.6, 41.6, 34.2,
4.8, 19.8, 19.3 ppm. 31P NMR (162 MHz, C
): δ ϭ 99.8 ppm.
ϭ ϩ60.9
D
(
c
ϭ
C
20
H
26
N
2
4 2
S
(
6 6
D
2
3
2
3
(
3
13
6 6
CyH) ppm. C NMR (100 MHz, C D
2
6 6
D
Ϫ1
25
IR (film): ν˜ ϭ 1653, 1261, 1091, 1021 cm . [α]
ϭ Ϫ10.7 (c ϭ
NaO
D
Method C: nBuLi (1.6  solution in hexanes, 1.05 mmol, 656 µL)
was slowly added to a stirred solution of bis(sulfonamide) 8
0
2
.49, THF). HRMS (ESI): calcd. for fragment C
93.0606; found 293.0587.
8
H
18
N
2
4 2
S :
(0.5 mmol) in dry THF (2.5 mL) at Ϫ78 °C under argon. Once the
addition of nBuLi was complete, the reaction mixture was stirred
Ligand 5adi: Method A, white powder (257 mg, 75%).
1
H NMR
at room temperature for 2 h. A Schlenk tube was charged with the
(400 MHz, C D ): δ ϭ 3.40Ϫ3.35 (m, 1 H, CyH), 2.92Ϫ2.83 (m, 1
H, CyH), 2.69 (s, 3 H, SO CH ), 2.67 (s, 3 H, SO CH ), 2.45 (s, 3
2 3 2 3
6
6
3
appropriate phosphorous dichloride (Cl
2
PR ) 11 (0.5 mmol) and
dry THF (1.5 mL), and was cooled to Ϫ78 °C. The lithium salt
solution was slowly added by means of a cannula. After 1 hour,
3 3
H, CH ), 2.44 (s, 3 H, CH ), 1.52Ϫ1.40 (m, 3 H, CyH), 1.22Ϫ1.17
(m, 1 H, CyH), 1.07Ϫ0.78 (m, 4 H, CyH) ppm. 13C NMR
the temperature was allowed to rise to room temperature, and the (100 MHz, C D ): δ ϭ 65.2, 63.7, 43.8, 41.3, 37.7, 37.3, 30.3, 30.0,
6
6
mixture was stirred overnight. THF was removed, and dry toluene
was added. The precipitate (LiCl) was removed by filtration (film): ν˜ ϭ 1634, 1260, 1157, 1105, 1054 cmϪ1. [α] 2D 5 ϭ Ϫ42.2 (c ϭ
24.0, 23.8 ppm. 31P NMR (162 MHz, C D ): δ ϭ 102.7 ppm. IR
6 6
through a PTFE membrane filter under argon. The solvent was
then removed under reduced pressure to obtain the product as a
yellow powder.
10 23 3 4 2
1.00, THF). HRMS (ESI): calcd. for C H N O PS : 344.0868 [M
ϩ
ϩ H]
10 22 3 4 2
; found 344.0863; calcd. for C H N NaO PS : 366.0687
ϩ
[M ϩ Na]
; found 366.0688.
1
1
Ligand 5aeh: Method C, white powder (265 mg, 96%). H NMR
Ligand 5ado: Method C, white powder (158 mg, 84%). H NMR
): δ ϭ 7.97Ϫ7.93 (m, 1 H, ArH), 7.17Ϫ7.07 (m, 4
(
400 MHz, C
6
D
6
): δ ϭ 8.02 (d, J ϭ 8.2 Hz, 2 H, ArH), 7.65 (d, (400 MHz, C
6
D
6
3562
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3557Ϫ3565

Chiral Phosphorus Ligands in Enantioselective Copper-Catalysed Conjugate Additions
FULL PAPER
H, ArH), 3.13Ϫ3.00 (m, 2 H, CyH), 2.83Ϫ2.78 (m, 1 H, CyH),
.57 (s, 3 H, SO CH ), 2.37 (s, 3 H, SO CH ), 2.20Ϫ2.18 (m, 1 H,
CyH), 1.49Ϫ1.18 (m, 4 H, CyH), 1.00Ϫ0.80 (m, 1 H, CyH), 1261, 1145, 1072 cm . [α]
0
1
130.7, 130.6, 130.3, 129.8, 129.3, 75.8, 73.8, 43.2, 41.6 ppm. 31P
NMR (162 MHz, C
): δ ϭ 108.2 ppm. IR (film): ν˜ ϭ 1640, 1329,
2
2
3
2
3
6 6
D
Ϫ1
25
D
ϭ Ϫ19.6 (c ϭ 1.00, THF). MS (FAB,
): δ ϭ glycerol): m/z (%) ϭ 475 (70), 375 (20), 353 (30), 289 (20), 274 (25),
30.8, 130.6, 130.4, 67.9, 65.9, 43.3, 37.4, 32.7, 29.4, 24.3, 24.1 ppm. 221 (35), 207 (50), 154 (90), 136 (100). HRMS (ESI): calcd. for
.55Ϫ0.45 (m, 1 H, CyH) ppm. 13C NMR (100 MHz, C
D
6 6
3
1
ϩ
P NMR (162 MHz, C
6
D
6
): δ ϭ 95.8 ppm. IR (film): ν˜ ϭ 1633,
C
22
H
23
N
2
NaO
4 2
PS : 497.0735 [M ϩ Na] ; found 497.0738.
Ϫ1
25
1
330, 1149, 1141, 1106, 1080, 1056 cm . [α]
D
ϭ Ϫ4.1 (c ϭ 1.00,
Ligand 5bdj: Method A, pale yellow powder (448 mg, 89%). 1
H
THF). MS (FAB, glycerol): m/z (%) ϭ 377 (100), 313 (45), 299 (20),
2
ϩ Na] ; found 399.0576.
NMR (200 MHz, C ): δ ϭ 7.57Ϫ6.85 (m, 15 H, ArH),
5.49Ϫ5.47 (m, 1 H, CHN), 5.13Ϫ5.09 (m, 1 H, CHN), 4.42Ϫ4.26
m, 2 H, CH Ph), 3.41 (br. s, 1 H, NH), 2.09 (s, 6 H, 2 ϫ SO CH
ppm. C NMR (50 MHz, C D ): δ ϭ 140.9, 139.7, 129.8, 129.4,
6 6
D
05 (30). HRMS (ESI): calcd. for C14
H
21
N
2
NaO
4
PS
2
: 399.0578 [M
ϩ
(
2
2
3
)
1
13
Ligand 5adj: Method A, yellow powder (365 mg, 90%). H NMR
6
6
3
1
(
400 MHz, C
H, CH ), 2.36 (s, 6 H, 2 ϫ SO
.30Ϫ1.26 (m, 2 H, CyH), 1.05Ϫ0.60 (m, 6 H, CyH) ppm.
NMR (100 MHz, C ): δ ϭ 129.1, 129.0, 128.6, 66.5, 43.1, 29.5,
3.6 ppm. 31P NMR (162 MHz, C
D ): δ ϭ 134.9 ppm. IR (film): found 504.1197; calcd. for C H N NaO PS : 526.1000 [M ϩ
6 6
23 26 3 4 2
6
D
6
): δ ϭ 7.14Ϫ7.00 (m, 5 H, ArH), 3.15Ϫ3.11 (m, 2 128.7, 127.9, 127.6, 70.7, 70.4, 47.9, 42.7, 42.0 ppm. P NMR
2
2
CH ), 2.18Ϫ2.10 (m, 2 H, CyH), (162 MHz, C D ): δ ϭ 101.4 ppm. IR (film): ν˜ ϭ 3371, 1635, 1336,
3
6
6
1
3
Ϫ1
25
1
C
1316, 1163, 1145, 1088, 1073 cm . [α]D ϭ Ϫ12.8 (c ϭ 1.00, THF).
ϩ
6
D
6
HRMS (ESI): calcd. for C H N O PS : 504.1181 [M ϩ H] ;
2
3
27
3
4
2
2
Ϫ1
25
ϩ
ν˜ ϭ 3392, 1653, 1159 cm . [α]
ϭ Ϫ3.4 (c ϭ 1.02, THF). HRMS
Na] ; found 526.1024.
D
(
ESI): calcd. for fragment C H N O S : 270.0708; found 270.0710.
8 18 2 4 2
Ligand 5ceh: Method C, pale orange powder (354 mg, 98%). 1
NMR (200 MHz, C D ): δ ϭ 7.60Ϫ5.75 (m, 20 H, ArH),
6 6
3.78Ϫ3.57 (m, 2 H, 2 ϫ CH), 1.97 (s, 3 H, ArCH ), 1.90 (s, 3 H,
3
H
Ligand 5beh: Method C, brownish powder (260 mg, 80%). 1
NMR (400 MHz, C ): δ ϭ 7.87 (d, J ϭ 8 Hz, 2 H, ArH), 7.85
d, J ϭ 8 Hz, 2 H, ArH), 7.26Ϫ7.14 (m, 6 H, ArH), 6.71Ϫ6.63 (m, ArCH ), 1.52Ϫ1.46 (m, 12 H, 4 ϫ CH ) ppm. 13C NMR (50 MHz,
H
6
D
6
(
4
5
2
3
3
H, ArH), 6.46Ϫ6.39 (m, 3 H, ArH), 6.28Ϫ6.24 (m, 1 H, ArH),
6 6
C D ): δ ϭ 141.9, 141.8, 136.9, 133.3, 132.9, 131.9, 130.9, 130.1,
.63 (dd, J ϭ 5.9 Hz, 1.18 Hz, 1 H, CHN), 4.95 (dd, J ϭ 5.8 Hz, 129.7, 128.8, 126.8, 127.4, 51.4, 25.0, 23.4, 21.2, 20.1. 31P NMR
.4 Hz, 1 H, CHN), 3.93Ϫ3.79 (m, 2 H, 2 ϫ CH), 1.91 (s, 3 H, (162 MHz, C D ): δ ϭ 129.4 ppm. IR (film): ν˜ ϭ 1632, 1596, 1342,
6
6
ArCH
3
), 1.87 (s, 3 H, ArCH
3
), 1.69Ϫ1.61 (m, 12 H, 4 ϫ CH
3
)
1261, 1201, 1161, 1089, 1027 cmϪ1. [α] 2D 5 ϭ Ϫ9.0 (c ϭ 1.00, THF).
ppm. 13C NMR (100 MHz, C
D ): δ ϭ 143.2, 141.8, 137.8, 129.7, HRMS (ESI): calcd. for C H N NaO PS : 744.2096 [M ϩ Na] ;
6 6
40 40 3 4 2
31
ϩ
1
28.8, 128.6, 127.3, 72.5, 70.9, 63.4, 48.8, 47.5, 21.1, 19.3 ppm.
P
found 744.2112.
NMR (162 MHz, C
6
D
6
): δ ϭ 110.1 ppm. IR (film): ν˜ ϭ 1599, 1559,
1
Ϫ1
25
Ligand 5ceo: Method C, yellow powder (342 mg, 98%). H NMR
1
(
6
348, 1157, 1089 cm . [α]
ESI): calcd. for C34
50.2250; calcd. for C34
found 672.2102.
D
ϭ ϩ35.0 (c ϭ 1.00, THF). HRMS
ϩ
6 6
(200 MHz, C D ): δ ϭ 8.42Ϫ8.38 (m, 2 H, ArH), 7.79Ϫ7.48 (m, 7
H, ArH), 7.30Ϫ6.92 (m, 10 H, ArH), 6.69Ϫ6.55 (m, 4 H, ArH),
H
41
N
3
O
4
PS
2
: 650.2276 [M ϩ H] ; found
ϩ
40 3 4 2
H N NaO PS : 672.2096 [M ϩ Na] ;
6
1
1
1
1
1
.12 (d, J ϭ 8.2 Hz, 1 H, ArH), 5.96 (d, J ϭ 8.2 Hz, 1 H, ArH),
1
3
.96 (s, 6 H, 2 ϫ ArCH
44.1, 137.3, 135.1, 133.0, 131.4, 131.3, 130.2, 128.7, 127.8, 127.5,
3 6 6
) ppm. C NMR (50 MHz, C D ): δ ϭ
Ligand 5beo: Method C, brownish powder (232 mg, 74%). 1
NMR (400 MHz, C ): δ ϭ 8.46 (t, J ϭ 7.3 Hz, 2 H, ArH), 8.04
H
D
6
31
6
25.7, 125.2, 120.0, 21.5 ppm. P NMR (162 MHz, C
6
D ): δ ϭ
6
(
(
d, J ϭ 8.2 Hz, 2 H, ArH), 7.71Ϫ7.67 (m, 2 H, ArH), 7.26Ϫ7.04
m, 6 H, ArH), 6.92Ϫ6.78 (m, 5 H, ArH), 6.64Ϫ6.49 (m, 4 H,
31.7 ppm. IR (film): ν˜ ϭ 1633, 1593, 1349, 1302, 1261, 1211, 1158,
Ϫ1
25
088 cm . [α]
D
ϭ Ϫ1.48 (c ϭ 1.01, THF). MS (FAB, glycerol):
ArH), 6.24Ϫ6.22 (m, 2 H, ArH), 5.42 (d, J ϭ 7.0 Hz, 1 H, CHN),
.23 (d, J ϭ 7.0 Hz, 1 H, CHN), 1.99 (s, 3 H, ArCH ), 1.94 (s, 3
H, ArCH ): δ ϭ 143.9, 142.7,
) ppm. 13C NMR (100 MHz, C
42.0, 139.7, 138.9, 137.1, 135.7, 130.7, 130.5, 130.4, 130.2, 139.4,
m/z (%) ϭ 698 (30), 599 (90), 438 (90), 282 (95), 267 (65), 177
100), 152 (80), 136 (45), 107 (30), 89 (60). HRMS (ESI): calcd. for
5
3
(
3
6
D
6
C
H
31
N
2
NaO
PS
2
: 721.1361 [M ϩ Na] ; found 721.1378.
ϩ
40
4
1
1
1
29.3, 129.2, 129.1, 127.0, 77.2, 74.3, 18.6, 17.2 ppm. 3 P NMR
): δ ϭ 107.6 ppm. IR (film): ν˜ ϭ 1348, 1156, 1088
ϭ ϩ29.5 (c ϭ 1.00, THF). HRMS (ESI): calcd. for
1
Ligand 5cdi: Method A, yellow powder (503 mg, 98%). H NMR
(
200 MHz, C
6 6
D ): δ ϭ 8.25Ϫ6.85 (m, 12 H, ArH), 2.64 (s, 3 H,
(
6 6
162 MHz, C D
Ϫ1
25
SO CH ), 2.61 (s, 3 H, SO CH ), 2.31 (s, 3 H, CH ), 2.26 (s, 3 H,
cm . [α]
D
2
3
2
3
3
1
3
ϩ
3 6 6
CH ) ppm. C NMR (50 MHz, C D ): δ ϭ 135.0, 131.4, 131.1,
28.7, 125.8, 125.2, 120.1, 40.3, 34.2 ppm. P NMR (162 MHz,
C
34
H
31
N
2
NaO
4
PS
2
: 649.1361 [M ϩ Na] ; found 649.1342.
3
1
1
Ligand 5bdi: Method A, pale yellow powder (415 mg, 94%). 1
H
6 6
C D
1
): δ ϭ 125.5 ppm. IR (film): ν˜ ϭ 1620, 1590, 1261, 1159, 1076,
NMR (200 MHz, C ): δ ϭ 7.58Ϫ7.53 (m, 2 H, ArH), 7.17Ϫ6.94
m, 8 H, ArH), 5.48 (d, J ϭ 5.8 Hz, 1 H, CHN), 5.09Ϫ5.05 (m, 1
H, CHN), 2.79 (s, 3 H, NCH ), 2.75 (s, 3 H, NCH ), 2.14 (s, 3 H,
SO CH ), 2.01 (s, 3 H, SO CH
) ppm. 13C NMR (50 MHz, C
δ ϭ 138.4, 137.8, 129.5, 129.3, 129.2, 129.1, 129.0, 128.9, 70.8, 69.1, (200 MHz, C
6
D
6
Ϫ1
25
021 cm . [α]
D
ϭ ϩ24.73 (c ϭ 1.01, THF). HRMS (ESI): calcd.
(
ϩ
for C24 NaO
H
24
N
3
4
PS
2
: 536.5607 [M ϩ Na] ; found 536.5671.
3
3
1
D
6
): Ligand 5cdo: Method C, golden powder (270 mg, 99%). H NMR
2
3
2
3
6
6
D
6
): δ ϭ 8.28Ϫ8.01 (m, 2 H, ArH), 7.83Ϫ7.52 (m, 5
H, ArH), 7.36Ϫ6.82 (m, 10 H, ArH), 1.91 (s, 3 H, SO CH ), 1.59
): δ ϭ 133.8,
133.6, 133.3, 132.9, 132.1, 131.9, 131.3, 130.2, 128.9, 128.7, 128.5,
4
1
2.6, 42.3, 37.8, 37.5 ppm. 31P NMR (162 MHz, C
12.5 ppm. IR (film): ν˜ ϭ 1602, 1146, 1079 cm . [α]
6
Ϫ1
D
6
): δ ϭ 116.9,
2
3
25
13
ϭ Ϫ3.8
2 3 6 6
(s, 3 H, SO CH ) ppm. C NMR (50 MHz, C D
D
(c ϭ 0.99, THF). MS (FAB, glycerol): m/z (%) ϭ 441 (100). HRMS
3
1
(
3
ESI): calcd. for fragment C16
91.0765.
H
20
N
2
NaO
4
S
2
: 391.0762; found
127.1, 126.9, 126.1, 125.5, 120.4, 43.1, 41.0, 40.0 ppm. P NMR
(162 MHz, C
): δ ϭ 129.8 ppm. IR (film): ν˜ ϭ 1632, 1590, 1345,
6 6
D
Ϫ1
25
1
153, 1093 cm . [α]
calcd. for C28
69.0724.
D
ϭ ϩ33.7 (c ϭ 1.00, THF). HRMS (ESI):
1
Ligand 5bdo: Method C, white powder (211 mg, 89%). H NMR
ϩ
H
23
N
2
NaO
4
PS
2
: 569.0735 [M ϩ Na] ; found
(200 MHz, C
6 6
D ): δ ϭ 8.38Ϫ8.28 (m, 1 H, ArH), 7.36Ϫ7.24 (m, 8
5
H, ArH), 7.22Ϫ7.15 (m, 2 H, ArH), 7.11Ϫ7.07 (m, 1 H, ArH),
1
7.05Ϫ6.86 (m, 3 H, ArH), 5.64 (d, J ϭ 7.2 Hz, 1 H, CHN), 5.52 Ligand 5cdj: Method A, yellow powder (489 mg, 85%). H NMR
(
SO
2 3 6 6
d, J ϭ 7.2 Hz, 1 H, CHN), 2.29 (s, 3 H, SO CH ), 2.05 (s, 3 H, (200 MHz, C D ): δ ϭ 8.10Ϫ6.80 (m, 17 H, ArH), 4.39 (s, 2 H,
CH
3
) ppm. 13C NMR (50 MHz, C
6
D
6
): δ ϭ 142.2, 141.3, 138.4,
CH
2
Ph), 2.15 (s, 3 H, SO
2
CH
3
), 2.10 (s, 3 H, SO
2
CH
3
) ppm.
13
C
2
Eur. J. Org. Chem. 2004, 3557Ϫ3565
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3563

C. Monti, C. Gennari, R. M. Steele, U. Piarulli
FULL PAPER
6 6
D
): δ ϭ 131.4, 131.1, 130.8, 129.8, 129.3, 121.1, 120.8, 109.9, 109.8, 109.6, 55.0, 54.9, 54.8, 54.6 ppm. 31P
NMR (50 MHz, C
29.0, 128.4, 128.2, 120.0, 40.9, 40.5, 25.9 ppm. P NMR
162 MHz, C
): δ ϭ 166.6 ppm. IR (film): ν˜ ϭ 3389, 1621, 1594, 1261, 1156, 1091 cm . [α]
31
1
(
6 6
NMR (162 MHz, C D
): δ ϭ 127.2 ppm. IR (film): ν˜ ϭ 1640, 1589,
Ϫ1
25
6
D
6
D
ϭ Ϫ13.17 (c ϭ 1.01, THF). HRMS
Ϫ1
25
ϩ
1
236, 1161, 994 cm . [α]
D
ϭ Ϫ1.8 (c ϭ 1.00, THF). HRMS (ESI): (ESI): calcd. for C38
H
37
N
H
3
O
8
PS
2
: 758.1760 [M ϩ H] ; found
ϩ
ϩ
calcd. for C29
H
27
N
3
O
4
PS
2
: 576.1181 [M ϩ H] ; found 576.1195.
758.1744; calcd. for C38
found 780.1543.
36
N
3
NaO PS : 780.1579 [M ϩ Na] ;
8 2
Ligand 5cdl: Method A, white powder (578 mg, 98%). 1H NMR
200 MHz, C ): δ ϭ 8.12 (d, J ϭ 8.6 Hz, 1 H, ArH), 7.90 (d,
J ϭ 8.6 Hz, 1 H, ArH), 7.75Ϫ7.67 (m, 2 H, ArH), 7.63Ϫ7.61 (m,
(
6 6
D
General Procedure for the Copper-Catalysed Conjugate Addition of
Et Zn to Cyclohexenone: In a dry Schlenk tube equipped with a
2
3
1
1
H, ArH), 7.54 (d, J ϭ 8.6 Hz, 1 H, ArH), 7.48 (d, J ϭ 8.6 Hz,
H, ArH), 7.25Ϫ6.90 (m, 8 H, ArH), 4.89Ϫ4.87 (m, 1 H, CH),
stirring bar and argon inlet, copper triflate (0.005 mmol, 1.8 mg)
was added to a solution of the ligand (0.11eq, 0.011 mmol) in dry
toluene (500 µL), and the mixture was stirred for 30 min. The reac-
tion mixture was cooled to Ϫ20 °C, and a solution of diethylzinc
.76 (d, J ϭ 6.7 Hz, 3 H, CH
3
), 1.70 (s, 6 H, 2 ϫ SO
2 3
CH ) ppm.
13
C NMR (50 MHz, C
27.5, 126.4, 52.0, 43.9, 40.4, 20.8 ppm. P NMR (162 MHz,
6 6
D ): δ ϭ 138.9, 130.6, 129.2, 129.1, 127.6,
31
1
(
1.1  in toluene, 0.22 mmol, 200 µL) was added, followed by 2-
cyclohexenone (0.1 mmol, 10 µL). The reaction was monitored by
TLC (hex/Et O, 8:2). The reaction was quenched with a saturated
aqueous solution of NH Cl after 5 h. A sample of the organic
phase was injected into the chiral GC for analysis [column: ME-
GADEX DACTBSβ, 25 m, film 0.25 µm; carrier: H , 70 kPa; injec-
tor: 200 °C; detector: 200 °C; oven temperature: 50 °C, 5 °C·min
to 150 °C; t : 14.8 (3R enantiomer) and 15.1 min (3S enantiomer)].
The organic phase was separated, washed with brine, dried with
Na SO , and the solvents evaporated under reduced pressure. Puri-
fication by flash chromatography (eluent: n-hexane/ethyl acetate,
5:5) gave pure 3-ethylcyclohexanone (12 mg) in 95% yield.
Ϫ1
6 6
C D .
): δ ϭ 107.9 ppm. IR (film): ν˜ ϭ 1630, 1588, 1153 cm
2
5
D
[α] ϭ Ϫ6.46 (c ϭ 0.99, THF). HRMS (ESI): calcd. for
2
ϩ
C
30
H
29
N
3
O
4
2
PS : 590.1337 [M ϩ H] ; found 590.1316.
4
1
Ligand 5cdk: Method A, white powder (442 mg, 75%). H NMR
2
(
1
CH
200 MHz, C ): δ ϭ 8.07Ϫ6.85 (m, 17 H, ArH), 4.90Ϫ4.79 (m,
H, CH), 1.69 (s, 6 H, 2 ϫ SO CH ), 1.50 (d, J ϭ 6.6 Hz, 3 H,
) ppm. 13C NMR (50 MHz, C
): δ ϭ 138.9, 131.2, 129.2,
6 6
D
Ϫ1
2
3
R
3
6 6
D
31
1
(
29.0, 128.4, 127.8, 127.0, 52.0, 44.2, 41.0, 20.8 ppm. P NMR
162 MHz, C
): δ ϭ 113.5 ppm. IR (film): ν˜ ϭ 1632, 1597, 1154
ϭ Ϫ1.8 (c ϭ 1.00, THF). HRMS (ESI): calcd. for
2
4
6 6
D
Ϫ1
25
cm . [α]
D
9
ϩ
C
30
H
29
N
3
O
4
PS
2
: 590.1337 [M ϩ H] ; found 590.1323.
1
Ligand 5cdm: Method B, pale orange powder (326 mg, 94%). H
NMR (200 MHz, C ): δ ϭ 7.75Ϫ7.65 (m, 8 H, ArH), 7.30Ϫ6.95
m, 14 H, ArH), 3.69Ϫ3.65 (m, 2 H, 2 ϫ CH), 2.10 (s, 6 H, 2 ϫ
) ppm. 13C NMR (50 MHz, C
SO CH ), 2.08 (s, 6 H, 2 ϫ CH ):
δ ϭ 137.6, 129.5, 129.1, 128.9, 57.6, 41.0, 22.1 ppm. P NMR
162 MHz, C
): δ ϭ 146.3 ppm. IR (film): ν˜ ϭ 1632, 1589, 1581,
6 6
D
Acknowledgments
(
We thank the European Commission for financial support (IHP
Network grant ‘‘CombiCat’’ HPRN-CT-2000Ϫ00014) and for a
postdoctoral fellowship to R. M. S. (‘‘Marie Curie’’ IEF grant
‘‘Modular Chiraphos’’ MEIF-CT-2003Ϫ500097). We would also
like to thank Merck Research Laboratories (Merck’s Academic De-
velopment Program Award to C. G.) and Universit a` degli Studi di
Milano for financial support and for a postdoctoral fellowship to
C. M. (Assegno di ricerca). We thank Prof. Johannes G. de Vries
(University of Groningen, DSM Research-Life Sciences) and Dr.
2
3
3
6 6
D
31
(
6 6
D
Ϫ1
25
1
155, 1074 cm . [α]
calcd. for C38
16.1801.
D
ϭ Ϫ2.5 (c ϭ 1.00, THF). HRMS (ESI):
H N NaO PS : 716.1783 [M ϩ Na] ; found
36 3 4 2
ϩ
7
Ligand 5cdn: Method B, pale orange powder (340 mg, 98%). 1
NMR (200 MHz, C ): δ ϭ 7.75Ϫ7.69 (m, 8 H, ArH), 7.30Ϫ7.18
H
6
D
6
(m, 10 H, ArH), 7.16Ϫ7.14 (m, 4 H, ArH), 3.70Ϫ3.68 (m, 2 H, 2 Andr e´ H. M. de Vries (DSM Research-Life Sciences) for helpful
ϫ CH), 2.11 (s, 6 H, 2 ϫ SO
C NMR (50 MHz, C D
6 6
4
2
CH
): δ ϭ 137.5, 129.1, 129.0, 128.8, 57.6,
0.9, 22.0 ppm. 31P NMR (162 MHz, C
): δ ϭ 146.4 ppm. IR
film): ν˜ ϭ 1652, 1634, 1581, 1261, 1155, 1073 cm . [α]
c ϭ 1.00, THF). HRMS (ESI): calcd. for C38
3
), 2.09 (s, 6 H, 2 ϫ CH
3
) ppm.
discussions. U. P. thanks the Dipartimento di Chimica Organica e
Industriale (University of Milano) for their hospitality.
13
6 6
D
Ϫ1
25
(
(
7
D
ϭ ϩ21.4
2
NaO PS :
[
[
1] [1a]
Transition Metals for Organic Chemistry, (Eds.: M. Beller, C.
H
36
N
3
4
Bolm), Wiley-VCH, Weinheim, 1998, vol. 1 and 2. [ Catalytic
Asymmetric Synthesis (Ed.: I. Ojima), 2nd ed., Wiley-VCH,
New York, 2000.
1b]
ϩ
16.1783 [M ϩ Na] ; found 716.1775.
1
Ligand 5cfi: Method A, yellow powder (588 mg, 84%). H NMR
2]
For a recent review on the use of chiral phosphorus ligands in
enantioselective hydrogenation, see: W. Tang, X. Zhang, Chem.
Rev. 2003, 103, 3029Ϫ3069.
(
1
2
200 MHz, C ): δ ϭ 8.50Ϫ8.40 (m, 2 H, ArH), 7.80Ϫ6.81 (m,
6 H, ArH), 5.80 (d, J ϭ 8.4 Hz, 2 H, ArH), 5.65 (d, J ϭ 8.5 Hz,
H, ArH), 2.99 (s, 3 H, OCH ), 2.95 (s, 3 H, OCH ), 2.39 (s, 3 H,
), 2.38 (s, 3 H, NCH ): δ ϭ
) ppm. 13C NMR (50 MHz, C
31.7, 130.3, 129.6, 128.8, 128.2, 126.2, 125.9, 125.7, 114.9, 113.3,
4.6, 54.4 ppm. 31P NMR (162 MHz, C
): δ ϭ 127.1 ppm. IR
6 6
D
[3] [3a]
3
3
M. van den Berg, A. J. Minnaard, R. M. Haak, R. Leeman,
NCH
1
5
3
3
6
D
6
E. P. Schudde, A. Meetsma, B. L. Feringa, A. H. M. de Vries,
C. E. P. Maljaars, C. E. Willians, D. Hyett, J. A. F. Boogers,
H. J. W. Henderickx, J. G. de Vries, Adv. Synth. Catal. 2003,
345, 308Ϫ323. [ A. Duursma, A. J. Minnaard, B. L. Feringa,
6
D
6
3b]
Ϫ1
25
(
film): ν˜ ϭ 1595, 1260, 1157, 1092, 1025 cm . [α]
ϭ Ϫ2.2 (c ϭ
D
[
3c]
Tetrahedron 2002, 58, 5773Ϫ5778.
B. L. Feringa, Acc.
0
.81, THF). HRMS (ESI): calcd. for C36
H
H
33
N
N
3
O
6
PS
2
: 698.1548 [M
Chem. Res. 2000, 33, 346Ϫ356. [ B. L. Feringa, M. Pineschi,
L. A. Arnold, R. Imbos, A. H. M. de Vries, Angew. Chem. Int.
Ed. Engl. 1997, 36, 2620Ϫ2622. [ R. Imbos, M. H. G. Bril-
man, M. Pineschi, B. L. Feringa, Org. Lett. 1999, 1, 623Ϫ626.
3d]
ϩ
ϩ H] ; found 698.1528; calcd. for C36
32
3
NaO
6
PS
2
: 720.1368
ϩ
[M ϩ Na] ; found 720.1395.
3e]
1
Ligand 5cgi: Method A, brownish powder (667 mg, 88%). H NMR
[3f]
A. H. M. de Vries, A. Meetsma, B. L. Feringa, Angew.
(
200 MHz, C
J ϭ 8.7 Hz, 1 H, ArH), 7.80Ϫ6.68 (m, 14 H, ArH), 5.71 (d, J ϭ
.5 Hz, 1 H, ArH), 5.37 (d, J ϭ 8.4 Hz, 1 H, ArH), 3.09 (s, 3 H,
6 6
D ): δ ϭ 8.51 (d, J ϭ 8.7 Hz, 1 H, ArH), 8.42 (d,
Chem. Int. Ed. Engl. 1996, 35, 2374Ϫ2376.
[4]
O. Huttenloch, E. Laxman, H. Waldmann, Chem. Eur. J. 2002,
8
8
, 4767Ϫ4780.
OCH
OCH
3
), 3.07 (s, 3 H, OCH
), 2.37 (s, 3 H, NCH ), 2.34 (s, 3 H, NCH
): δ ϭ 131.8, 129.9, 129.7, 126.5, 126.3, 126.0, 125.7,
3
), 3.01 (s, 3 H, OCH
3
), 2.78 (s, 3 H,
[5] [5a]
[5b]
M. T. Reetz, T. Sell, Tetrahedron Lett. 2000, 41, 6333Ϫ6336.
) ppm. 1 C NMR
3
3
3
3
C. Claver, E. Fernandez, A. Gillon, K. Heslop, D. J. Hyett,
(50 MHz, C
6
D
6
A. Martorell, A. G. Orpen, P. G. Pringle, Chem. Commun.
3564
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org Eur. J. Org. Chem. 2004, 3557Ϫ3565

Chiral Phosphorus Ligands in Enantioselective Copper-Catalysed Conjugate Additions
FULL PAPER
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[
[
[
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[
6c]
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941Ϫ7943.
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hedron Lett. 2002, 43, 1189Ϫ1191.
[
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[
7b]
1
151Ϫ1157.
A. Alexakis, C. Malan, L. Lea, C. Benhaim,
[
[
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[7c]
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[
7d]
4
2
011Ϫ4027.
579Ϫ2581.
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[
A. Alexakis, J. Burton, J. Vastra, C. Benhaim,
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[
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M.
[
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[
[
8] [8a]
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[8b]
[
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[19]
[20]
[21]
[22]
[
[
10]
11]
[
11a]
for enantioselective catalysis, see:
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S. R. Gil-
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Eur. J. Org. Chem. 2004, 3557Ϫ3565
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3565